Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin.

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Lehtisalo M, Keskitalo JE, Tornio A, Lapatto-Reiniluoto O, Deng F, Jaatinen T, Viinamaki J, Neuvonen M, Backman JT, Niemi M

Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin.

Clin Transl Sci. 2020 Nov;13(6):1236-1243. doi: 10.1111/cts.12809. Epub 2020 May 26.

PubMed ID

32453913 [ View in PubMed

]

Abstract

Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 x 10(-5) ) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 microM, whereas allopurinol showed no inhibition with concentrations up to 200 microM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Febuxostat	ATP-binding cassette sub-family G member 2	Protein	Humans	No	Inhibitor	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Abemaciclib Febuxostat	The excretion of Abemaciclib can be decreased when combined with Febuxostat.
Afatinib Febuxostat	The excretion of Afatinib can be decreased when combined with Febuxostat.
Allopurinol Febuxostat	The excretion of Allopurinol can be decreased when combined with Febuxostat.
Apixaban Febuxostat	The excretion of Apixaban can be decreased when combined with Febuxostat.
Binimetinib Febuxostat	The excretion of Binimetinib can be decreased when combined with Febuxostat.